Ataxia telangiectasia (AT) is a complex, multisystemic human genetic disease with particular significance to the radiation biologist because of its extreme cellular radiation sensitivity. Although there has been considerable investigation into possible mechanisms for this sensitivity, and gene cloning and mapping have been aggressively pursued, the gene(s) responsible for the AT defect has not yet been identified. In this proposal, we employ a strategy using AT as a model system exhibiting a low background of radiation resistance to study genes that may affect radiation sensitivity and may be AT complementing, or downstream of the AT locus. We have used vector-mediated gene transfer with a cDNA expression library that contains Epstein Barr virus (EBV) oriP sequences and a selectable marker to transform radiation-sensitive AT5BIVA cells. By selection with large fractions of ionizing radiation, we have isolated a clone of transformed AT cells expressing "wild-type" fibroblast radiation sensitivity (ATCL2-11). Plasmid rescue and polymerase chain reaction amplifications permitted the identification of seven candidate cDNAs present in these transformed cells. In the performance of experiments proposed in this grant, we will identify and characterize the gene(s) responsible for modifying the radiation sensitivity of AT cells. The results of these investigations should provide insight into molecular factors affecting radiation sensitivity, and possible, into the nature of the AT cellular defect responsible for the acute radiation sensitivity of AT.